Lymphoproliferation disorder in mice explained by defects in Fas antigen that mediates apoptosis

Abstract

Fas antigen is a cell-surface protein that mediates apoptosis. It is expressed in various tissues including the thymus and has structural homology with a number of cell-surface receptors, including tumour necrosis factor receptor and nerve growth factor receptor. Mice carrying the lymphoproliferation (lpr) mutation have defects in the Fas antigen gene. The lpr mice develop lymphadenopathy and suffer from a systemic lupus erythematosus-like autoimmune disease, indicating an important role for Fas antigen in the negative selection of autoreactive T cells in the thymus.

Functional promoter haplotypes of the human FAS gene are associated with the phenotype of SLE characterized by thrombocytopenia

“…21 The less severe lpr cg strain expresses a nonfunctional Fas caused by a missense mutation within the death domain encoding part of the Fas gene. 22 The gld mouse has a missense mutation in the extracellular domain of FasL, which abrogates its function. 23 The phenotype of these mutations, when bred onto the autoimmune MRL background, is very similar.…”

Sensitivity to Fas-mediated apoptosis is null or weak in B-cell non-Hodgkin's lymphomas and is moderately increased by CD40 ligation

“…One of the major pathways regulating apoptosis in lymphoid cells appears to be mediated by the Fas antigen (APO-l/CD95), a 45-kDa membrane protein belonging to the tumour necrosis factor receptor (TNFR) superfamily (Itoh et al, 1991;Oehm et al, 1992;Armitage, 1994). Mice deficient in Fas or its ligand (FasL) are known as Ipr and gld mice respectively (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). They develop massive lymphadenopathy, splenomegaly, B-cell activation and autoimmunity owing to unscheduled lymphocyte accumulation (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994).…”

“…Mice deficient in Fas or its ligand (FasL) are known as Ipr and gld mice respectively (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). They develop massive lymphadenopathy, splenomegaly, B-cell activation and autoimmunity owing to unscheduled lymphocyte accumulation (Watanabe-Fukunaga et al, 1992;Lynch et al, 1994). In addition, Fas has also been demonstrated to act as a tumoursuppressor gene in some particular conditions (Peng et al, 1996).…”

Malignant and reactive cells from human lymphomas frequently express Fas ligand but display a different sensitivity to Fas-mediated apoptosis

“…guard against emergence of auto-reactive lymphocytes. [11][12][13][14] Ipr mutant mice harbor either an early transposable element or a mutation in the Fas gene, which either severely reduce Materials and methods the expression of a full size Fas transcript, or abolish its ability Tissue sampling and study design and Fas mRNAs using reverse transcriptase-polymerase chain CD21, CD22, CD23, CD24, and immunoglobulin light chains, ␦, , ␥, and ␣ immunoglobulin heavy chains), T cells (CD2, CD3, CD4, CD5, CD7, CD8) and ReedSternberg/activated cells (CD30). For double-color flow cyto-CAT GAA CCC ATG TTT GCA-3′ (nucleotide positions: 2118-2142)) for Fas.…”